Toxoplasmosis: A Link To Mental Illness

Toxoplasmosis is ubiquitous and capable of infecting virtually if not all mammalian species. Reports on latent toxoplasmosis have shown to affect one- third of the total population. The incidence of toxoplasmosis differs, however, with underdeveloped countries having a higher incidence than developed countries. While many people throughout the world are infected with Toxoplasma gondii and the prevalence of mental illness is rare in comparison, Toxoplasma gondii should at least be considered as contributing factor in mentally ill people who may have been exposed to Toxoplasma gondii. The CNS is mainly affected by toxoplasmosis, placing certain groups of individuals at higher risk over others. Toxoplasma gondii infection has been linked with psychiatric illnesses however, research on the causal pathway is limited and therefore not clearly developed. The aim of this review is to discuss the link between Toxoplasmosis and mental illness.

Introduction

Psychosis burdens many people worldwide. Nearly hundred thousand (100,000) young people experience psychotic symptoms each year, and a ratio of 1:100 people will experience symptoms at some time in their lives. Estimation revealed that psychiatric disorders amounts to approximately 10% of the disease burden of low- and middle-income countries [1] Psychosis is characterized primarily by symptoms of either delusions, hallucinations or thought disorder [1], which includes perceiving things as strange or seeing things that are not there. Psychotic episodes in childhood are strong predictors of schizophrenia later in life [2].

Psychiatric illnesses that include psychotic symptoms such as schizophrenia, schizoaffective disorder, bipolar disorders with psychotic features, depression with psychotic features and even anxiety disorders like Obsessive Compulsive Disorder (OCD) [3]. One of such environmental factors that has recently been explored in leading to psychotic symptoms is the contribution of parasitic infections. Toxoplasma gondii infection has been linked with psychiatric illnesses however, research on the causal pathway is limited and therefore not clearly developed. As research has shown, Toxoplasmosis could be related to developing a psychotic disorder or alternatively Toxoplasmosis could cause psychotic symptoms by affecting similar brain regions and clinical manifestations might mimic a disorder like schizophrenia [4].

Schizophrenia may well be a syndrome with many forms. If one were to consider an infection related form, a careful diagnosis might lead to increased treatment options. While many people throughout the world are infected with Toxoplasma gondii and the prevalence of psychosis is rare in comparison, Toxoplasma gondii should at least be considered as contributing factor in mentally ill people who may have been exposed to Toxoplasma gondii. However, the combination of genomic risk for schizophrenia and an infection is a possible model for a gene-environment type cause for illness. The brain is one common area where Toxoplasma gondii cysts form, affecting a large variety of cells with different functions. This could be of help in shedding more light to the etiology of psychiatric illnesses. One biological mechanism is the effects of Toxoplasma gondii on hippocampus and amygdala.

Toxoplasma infection (Toxoplasmosis) is caused by the protozoan parasite Toxoplasma gondii. Felines are the definitive/final host which shed the oocyst in feaces and hereby transmit the infective stage to the other intermediate hosts. It has been estimated that about one-third of the populace are infected with Toxoplasma gondii [5], with a world-wide varying sero-prevalence. The differences observed in prevalence rates throughout the world may be linked to environmental and behavioural factors such as food and water handling culture, macro and microclimate, landscape, soil exposure, all of which vary widely between countries.

Toxoplasma gondii can be transmitted to humans in different ways. First is food-borne infection, which can occur by eating contaminated meat (particularly pork or beef), ingestion of cysts after touching contaminated raw or undercooked meat and improper hand-washing or by eating food prepared with utensils or cookware that are contaminated and/or not properly cleaned. Intermediate hosts become infected by consuming soil, food and water contaminated with Toxoplasma gondii oocyst. Evidence from epidemiologic studies suggests that in places such as Ethiopia and France, where sero-prevalence is high and eating of partially cooked beef is customary, tissue cysts are the main sources of infection [4].

Another method of transmission can occur through contact, human- cat contacts. Cats are the known final host of the parasite and are known to shed the infective stage known as oocyst. The number of cat owner has increased by about 50% in the last 20 years there by increasing the human- cat contact [4]. The United States ranks highest among countries with cat populations, followed by China, Russia, Brazil, Nigeria and France [6]. Evidence suggests that nearly 1% of cats shed oocysts per minute [32].

Additionally, transmission can also occur from mother to child (congenital) which is known as vertical transmission or through blood transfusion, which is also a possible model of transmission [13]. Congenital toxoplasmosis causes the highest burden of disease among humans who are infected with Toxoplasma gondii [7].

Countries where high consumption of raw/ undercooked meat, high level of human-cat contact and low level of hygiene is common have reported a high prevalence of Toxoplasmosis. This countries includes France (47% prevalence), Tanzania (46% prevalence) and Nigeria (38% prevalence) [8]. In these regions there is an abundance of stray cats and in some the tropical climate is favorable to the survival of the oocyst, which is essential for transmission [9].

It has been estimated that not less than 60 million of the total population in the United State are infected with Toxoplasma gondii making it the third leading cause of food borne illness [10]. Infections with Toxoplasma gondii amount to not less than 3,000 deaths annually [1]. About four hundred (400) to four thousand (4,000) cases of congenital toxoplasmosis are reported annually [11]. Among those born with congenital toxoplasmosis 9% of cases have significant visual impairment. The rates of visual impairment from congenital toxoplasmosis in the three to four years after birth are much lower in U.S.A as compared to Europe (29%), Nigeria (23%) and Brazil (87%) [12].

The CNS is mainly affected by toxoplasmosis, placing certain groups of individuals at higher risk over others. The population at risk for toxoplasmosis includes infants whose mothers have been infected immediately either anti-natal or post-natal as well as patients who are immune-compromised, i.e. HIV positive patients, chemotherapy patients, those taking immunosuppressive medication, and organ transplant recipients [12]. Toxoplasma infection is a leading cause of death among patients concurrently infected with HIV [12].

Clinical manifestations of Toxoplasma gondii infection vary based on the health status of the infected individual. Healthy individuals who are infected may not be aware since their immune system is strong enough to prevent illness [13]. Those who are symptomatic upon initial infection may experience signs like aches and pains, fever or tiredness that typically resolve within a few weeks if left untreated [10].

Toxoplasma gondii infection is diagnosed by either serologic testing, genetic testing through polymerase chain reaction (PCR) or through parasite isolation in body tissue or fluids [14]. Serologic testing is the widely used diagnostic test, and is done to test for the presence of IgG and IgM antibodies. The presence of IgG antibodies against Toxoplasma reveals a previous exposure with the parasite, however does not indicate when it occurred, whereas IgM antibodies against Toxoplasma indicate an acute or recent infection. Distinction between acute and latent infection is most important in cases where the woman is pregnant or the individual is immunosuppressed. Antibody testing against Toxoplasma is readily available in most developed countries and routinely tested for in pregnant women where the prevalence of infection is high [1].

Lifecycle of Toxoplasma gondii

Schizogony, an asexual form of reproduction and gametogony, a sexual form of reproduction occurs in the cats and other felids thus making cats and other felids the definitive hosts. The cats shed or passes out sporulated oocysts alongside feaces in the environment. The cats gets infected by ingesting bradyzoites, tachyzoites or oocyts. Even though the time at which they shed oocysts varies according to the stage of the lifecycle ingested while the non-felids which includes human or mice are the intermediate hosts in which schizogony (asexual reproduction) similar to the cycle in cats occur.

Infection in cat is through ingestion of the three lifecycle stages; however, the life cycle ingested determines the pre-patent period. Three to Ten (3-10) days of consuming the tissue cyst leads to the shortest pre-patent period, and more than 18 days of consuming the oocyst leads to the longest pre-patent period [15]. During the acute infection, the tachyzoite is seen. Tachyzoites replicate through endodyogeny and this occurs every six (6) to eight (8) days. They replicate within the parasitophorous vacuole. The union with the endo-lysosomal pathway of the host is avoided by this vacuole [16].

In the expression of host genes, profound effects are induced by the parasites which includes molecules involved in signal transduction pathways [17]. All the cells found within the body can be infected by the tachyzoites. During an acute stage infection, in an immune-competent patient, tachyzoites are removed within few weeks. The tachyzoites differentiates into the bradyzoites which replicates slower than the tachyzoites and seen only in infections that are chronic. The host cells don’t get ruptured during the replication of the bradyzoite. Three days after the infection, bradyzoites can be found in the brain [11] (Figure 1).

Figure 1: Toxoplasma gondii Life-cycle.
Source: [18].

Innate immune responses to Toxoplasma gondii infection

After the parasite acquisition by the intermediate host, the parasite enters the enterocytes and reproduces which then leads to lysing of the host cells and the release of tachyzoites. Parasites can also crisscross the epithelial cells without damaging it due to their mode of movement [17] Toxoplasma infected cells of the small intestine secretes chemokine. Upon infection, there is invasion of the dendritic cells/ macrophages thereby spreading the infections to the brain [17].

Role of monocytes and neutrophils to Toxoplasma gondii infection

According to [19], “the role of monocytes were clearly stated and said to play a major part in mucosal immunity to Toxoplasma gondii by constraining the growth of the parasite through Nitric oxide (NO) production”.

Upon infection, neutrophils as the first cells to reach the infection site secretes IL-12 through the presence and absence of oxygen and in turn kills the parasite directly. Even though neutrophils have a protective role in mucosal immunity. A study by [19] revealed that neutrophils can also have a detrimental pathological effects.

The function of DCs in Toxoplasma gondii infection innate immune response

Dendritic cells (DCs) plays a vital role in integrating the innate immune response and links the innate and adaptive immunity. At the site of infections, the DCs are the initial Antigen Presenting cells. The parasite can infect the DCs, multiply there and are then processed for antigen presentation [19].

activation of the recruited monocytes.

The function of TLR’s in Toxoplasma gondii infection innate immune response

Numerous Toll like receptors (TLRs) plays a role in the detection of Toxoplasma gondii [20]. The production of IL-12, an important induction of innate immunity is stimulated by the TLR2 by recognizing profilin, a protein used in the parasite movement across host cells during invasion. TLR2 can as well play a role in the inhibition of immunopathology by modifying IFN-γ secretion by NK cells [20].

Adaptive immune response to Toxoplasma gondii infection

Antigen presenting cells are the main initiators of the adaptive immune response. The APCs helps the host to recognize an antigen through pattern recognition receptors which induces the IL-12 secretion. And then induce Nk cells, CD4+ and CD8+ T cells to produce IFN-γ [21]. “CD8+ T cells play a vital part in the defensive immunity to Toxoplasma gondii.

Intra-cerebral immune response

During the acute stage of the infection, the parasite can infect the neural system (neurons, microglial) and then persist majorly in the neurons. During the infections CD4+ and CD8+ T cells are recruited in the brain [22], which in turn leads to the secretion of chemokines and cytokines in response to the parasitic infections [22]. During the first week of infection, the cytotoxic T cells levels are increased in the brain while during the decline in the level of parasitemia, the CD8+ T cells persists at low levels in the brain transitioning from acute to chronic [23].

Immuno-regulation to Toxoplasma gondii infection

IL-10 is an anti-inflammatory cytokine, plays an important part throughout the chronic phase of the infection by limiting the inflammatory response [22] and thereby preventing the production of “IL-12, IFN-γ, TNF-γ and IL-6”in the brain. As a result of IL-10 depletion in the brain, there is a rise in the both macrophages and CD4+ T cells causing a fatal inflammatory response which points out the important role IL-10 plays in limiting inflammation.

Stages of toxoplasmosis

Different forms of Toxoplasmosis have detrimental effects on human health. The infection is opportunistic in nature and associated with immunosuppressive conditions [24]. Few adults that are exposed develop clinical signs to this disease while symptoms develops when cell destruction occur due to the multiplying tachyzoites , which mostly affects the brain, liver, lung, skeletal muscles and eyes. All forms of toxoplasmosis are a serious socio-economic burden throughout the world [25]. After a short phase of acute toxoplasmosis, the infection becomes latent and cysts are formed in the CNS and the muscles. There are different forms of toxoplasmosis in human.

Acquired toxoplasmosis

The acquired stage of toxoplasmosis is categorized by the occurrence of Toxoplasma gondii tachyzoites in blood or other tissues. The tachyzoites proliferates in various organs after ingestion of the parasite and the parasite forms cysts in the brain and establishes a chronic infection in humans and rats [5]. Symptoms of acute toxoplasmosis are usually mild and harmless, sometimes asymptomatic, while symptoms such as enlarged lymph nodes, fever, and headache [26]. At this stage, the hormonal and mental disorder may occur after variety of brain cells, including astrocytes and neurons have been infected. The acquired toxoplasmosis comes with clinical manifestations like Lymphadenopathy.

Chronic toxoplasmosis

Chronic toxoplasmosis develops when acute toxoplasmosis persist for many years. During this phase, the parasite lodges in the brain and muscles hidden from the host immune system. In most cases, all symptoms disappears within weeks or months and develop instead into the fourth latent form [5]. Males diagnosed with chronic toxoplasmosis were found to be thoughtful, bored easily, have low self-confidence and withdraw while females with chronic infections were self-sufficient, more outgoing, socially participative, cordial and show greater self-esteem [27].

Latent toxoplasmosis

Latent toxoplasmosis can influence rodents and human behaviour and phenotype [25]. The influences in rodents are termed parasite manipulation and human by parasite constraints. Rodents are the most common intermediate host for Toxoplasma gondii, thus manipulation hypothesis proposed that a parasite may adjust its host behaviour for its own profit, by increasing its chance of spreading. Human are dead-end hosts for Toxoplasma gondii, due to the inability of Toxoplasma gondii to develop into cysts in human. In Toxoplasma gondii, inactive infection ensues in the form of tissue cysts located in the brain or other organs. Psychiatric conditions such as schizophrenia, bipolar disorder and suicidal behaviour have been interrelated to latent Toxoplasma gondii infection. Long term personality change was observed in humans with latent infections of Toxoplasma gondii [28]. Also, studies have demonstrated that latent toxoplasmosis may induce behavioural changes in animal models and [29].

Congenital Toxoplasmosis (CTs)

Congenital Toxoplasmosis develops as an effect of a primary infection with Toxoplasma gondii following maternal transmission, in which the organism cross through the placenta thereby infecting the foetus [30]. Congenital infections acquired in the second and third stages of pregnancy are less severe than those acquired during the first trimester. Once there is an infection during pregnancy, it can lead to abortion or congenital effects on the foetus [30]. CTs has a detrimental effect on the growth if infants [11].

Cerebral toxoplasmosis

Cerebral toxoplasmosis is normally due to the recrudescence of a latent infection in the brain. It was reported by [31], that “cerebral Toxoplasmosis is the most common opportunistic disease in AIDS patients in both developed and underdeveloped countries”. Psychiatric conditions such as schizophrenia, bipolar disorder and suicidal behavior have been linked to latent Toxoplasma gondii are prominent in immune-compromised persons with AIDS in whom latent infections have been reactivated.

Toxoplasmosis and human behaviour

Toxoplasma gondii is the most significant model for studying the manipulation of a parasite on human behaviour as a result of its function in the cause and development of some fundamental psychiatric diseases like schizophrenia. Infected men with Toxoplasma gondii had been seen to tidy clothes lesser than uninfected men, and the opposite in the case of infected and uninfected women [25]. In sociability, infected men have lower score than the infected women who scored higher. Suspiciousness is also said to be higher in infected rural male compared to their non-infected peers [32].

Toxoplasmosis and schizophrenia

Schizophrenia is a chronic, debilitating condition which affects approximately 1% of the worldwide population [33]. It is a heterogeneous complex neuropsychiatric disorder which is accompanied with an uncertain etiology [34]. Environmental factors had appeared to increase the risk of schizophrenia apart from genetics which had strong contribution. Studies have established that in schizophrenic patients, the prevalence of Toxoplasma infection is uncommonly high, knowing that Toxoplasma gondii is a prime candidate in contributing to schizophrenia risk, and now known as a possible cause of this disease. This showed strong association between schizophrenia and Toxoplasma infection and toxoplasmosis is probably a very important (though not limited to this alone) cause of schizophrenia [4]. Anti- Toxoplasma antibodies were first detected in the blood samples of US soldiers that were later demilitarized because of the mental disorder noticed in them in 6 months. The genetic-risk factors and other environmental factors have been seen to be lesser than the schizophrenia-associated risk factors of Toxoplasmosis [3] reported a meta-analysis of 38 studies that increased prevalence of antibodies to Toxoplasma gondii is associated with individuals with schizophrenia with an overall OR 2.71 (95%CI: 1.93-3.80). Infected individuals with Toxoplasma show more severe positive schizophrenia (hallucination, delusions) than uninfected patients.

Toxoplasmosis and depression

There are about 350 million worldwide living with depression [35]. A study showed that psychiatric patients suffering from depression have significantly higher sero-prevalence of infection with Toxoplasma gondii that controls subjects without depression in the general population of the same city [36]. In a study of pregnant women in the USA, pre-natal depression was associated with Toxoplasma gondii titers in infected women [37]. In addition, the report of a 32 year old male suffering from depression with Toxoplasma gondii sero-positivity who responded to only anti-depressant treatment after an adequate treatment for Toxoplasma gondii [38], supports the potential role of Toxoplasma gondii in depression.

Toxoplasmosis and other mental disorders

A study showed a significant association between IgM antibodies level to Toxoplasma gondii and a life account of suicide attempt [7], found increased level of IgM and not IgG antibodies to Toxoplasma gondii in individuals with a past record of suicide attempt and this suggests that suicide behaviours are not exclusively correlated with contacts with the organisms but also to the incidence of reactivation of a quiescent infection. A sample of 71 subjects were studied and this showed a higher prevalence of latent Toxoplasmosis in Alzheimer Diseases (AD) (n=34) compared with non-demented control (44.1% and 24.3% respectively, P=0.005) [39].

Conclusion

Several studies links the exposure to Toxoplasmosis as a risk factor of vast array of neuropsychiatric symptoms including schizophrenia. The effects of Toxoplasma infection on the cytokine, neuro-inflammation, neuro-degeneration and behaviour are beginning to be understood. Toxoplasma gondii might affect the brain through local and systemic inflammation. This study helps us to understand the possible link between Toxoplasmosis and mental illness.

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